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IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin.

ABSTRACT: The IL-1 family members IL-36? (IL-1F6), IL-36? (IL-1F8), and IL-36? (IL-1F9) and the receptor antagonist IL-36Ra (IL-1F5) constitute a novel signaling system that is poorly understood. We now show that these cytokines have profound effects on the skin immune system. Treatment of human keratinocytes with IL-36 cytokines significantly increased the expression of CXCL1, CXCL8, CCL3, CCL5, and CCL20, potent chemotactic agents for activated leukocytes, and IL-36? injected intradermally resulted in chemokine expression, leukocyte infiltration, and acanthosis of mouse skin. Blood monocytes, myeloid dendritic cells (mDC), and monocyte-derived DC (MO-DC) expressed IL-36R and responded to IL-36. In contrast, no direct effects of IL-36 on resting or activated human CD4(+) or CD8(+) T cells, or blood neutrophils, could be demonstrated. Monocytes expressed IL-1A, IL-1B, and IL-6 mRNA and IL-1? and IL-6 protein, and mDC upregulated surface expression of CD83, CD86, and HLA-DR and secretion of IL-1? and IL-6 after treatment with IL-36. Furthermore, IL-36?-treated MO-DC enhanced allogeneic CD4(+) T cell proliferation, demonstrating that IL-36 can stimulate the maturation and function of DC and drive T cell proliferation. These data indicate that IL-36 cytokines actively propagate skin inflammation via the activation of keratinocytes, APC, and, indirectly, T cells.

SUBMITTER: Foster AM

PROVIDER: S-EPMC4048788 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin.

Foster Alexander M AM Baliwag Jaymie J Chen Cynthia S CS Guzman Andrew M AM Stoll Stefan W SW Gudjonsson Johann E JE Ward Nicole L NL Johnston Andrew A

Journal of immunology (Baltimore, Md. : 1950) 20140514 12

The IL-1 family members IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) and the receptor antagonist IL-36Ra (IL-1F5) constitute a novel signaling system that is poorly understood. We now show that these cytokines have profound effects on the skin immune system. Treatment of human keratinocytes with IL-36 cytokines significantly increased the expression of CXCL1, CXCL8, CCL3, CCL5, and CCL20, potent chemotactic agents for activated leukocytes, and IL-36α injected intradermally resulted in c ...[more]

PMID: 24829417

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Project description:In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36α, IL-36β and IL-36γ are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36γ. This cytokine was strongly induced by IL-17A and, together with IL-17A, efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors. Both IL-36γ and IL-17A induced cell proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 and NF-κB, respectively. We highlighted the intense IL-17A- and IL-36γ -dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. IL-17A or IL-36γ showed in HDMECs a synergic activity with TNF-α by potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36γ and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived IL-36γ represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but did not act on expression of adhesion molecules in HDMECs. On the other hand, inhibition of IL-36γ released by IL-17A-treated keratinocytes impaired either proliferation or ICAM-1 expression both in HDMECs and in an in vivo murine model of psoriasis. Taken together, our data demonstrated that IL-17A and IL-36γ are highly involved in endothelial cells/keratinocytes crosstalk in inflammatory skin conditions.

Dataset Information

IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin.

Publications

IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin.

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